Opiates remain among the most useful and important class of drugs in medicine, but not without problems. The recognition of the importance of treating pain has led to an increase in their overall use and, with it, an increase in diversion an abuse. Drugs capable of producing analgesia lacking these unwanted actions would be a major advance in treating pain and minimizing drug abuse. Our laboratory has synthesized a series of analogs targeting a new opioid site that have a superior pharmacological profile. They are potent analgesics, as much as 100-fold that of morphine, and yet they display no respiratory depression, physical dependence, reinforcing behavior or cross tolerance to morphine. Our goal in this proposal is to further expand the structure-activity of these compounds by using two scaffolds that have not been examined previously on this target. We also propose to design and synthesize additional chemical probes suitable for further exploring the pharmacology of opioids and the biochemical mechanisms of their actions. This work will focus upon the generation of novel radiolabeling techniques to permit the identification of potential new targets and affinity labels.